Study does not detect herd immunity associated with live attenuated vaccine

Action Points

Note that this cluster-randomized trial found no difference in influenza rates in communities receiving a live-attenuated intranasal vaccine (FluMist) versus those receiving an inactivated injectable vaccine.

Be aware that the FluMist intranasal vaccine is not recommended in the U.S. for the 2016-2017 flu season due to concerns about efficacy.

The trivalent FluMist influenza vaccine delivered by nasal spray performed as well as an injectable version in a cluster randomized clinical trial, researchers are reporting.

But the intranasal, attenuated-virus vaccine did not demonstrate an expected edge in efficacy, according to Mark Loeb, MD, chair and director of the division of infectious diseases of McMaster University in Hamilton, Ont., and colleagues.

But the Canadian data might not bear directly on the controversial decision, outside experts told MedPage Today.

"It looks to me like a very well-done study," commented William Schaffner, MD, professor and chair of the preventive medicine at Vanderbilt University in Nashville.

But Schaffner told MedPage Today that the study used a live attenuated vaccine that has a key difference from the one that the ACIP was concerned about -- it's missing the extra influenza B strain -- and the years covered by the analysis also differed.

Indeed, "the paper adds only a little to the picture," commented Andrew Pavia, MD, chief of the division of pediatric infectious diseases at the University of Utah in Salt Lake City.

"It is a very different study design, in a unique set of communities, and it was designed to look at whether LAIV induced better protection of the community when vaccinating children, not really to look at absolute efficacy," Pavia told MedPage Today by email.

As well, he said, "they used trivalent vaccines, and one concern has been that the years with low efficacy for LAIV in the U.S. have all been since going to quadrivalent and have been H1N1 years" -- seasons in which the predominant circulating strain was influenza A (H1N1).

Evaluating herd protection is difficult, the researchers noted, because it is usually not possible to assign all the children in a community to one or the other vaccine. To overcome that issue, the team turned to 52 Hutterite colonies in Alberta and Saskatchewan.

Hutterites are Anabaptist Christians who, like Mennonites and Amish, trace their religious roots to the 16th century reformation. In Canada, Hutterites live communally in small groups and are relatively isolated, Loeb and colleagues noted, although influenza is regularly introduced into the Hutterite communities.

Participating communities were randomly assigned to use either the nasal spray or the injectable vaccines for their children over three flu seasons -- 2012-13, 2013-14, and 2014-2015. The primary outcome was the incidence of lab-confirmed flu among all community residents, vaccinated or not.

The researchers found that average vaccine coverage was similar -- 76.7% for children in the nasal spray communities and 72.4% for those in the injectable vaccine communities -- and there was little difference in the rate of flu among the vaccinated children, with a nonsignificant hazard ratio of 0.97.

In communities assigned to the nasal spray, flu occurred in all residents at a rate of 5.3%, compared with 5.2% in communities whose children got the injectable vaccine. The hazard ratio was 1.03, with a 95% confidence interval from 0.85 to 1.24.

"It couldn't get much closer," Loeb told MedPage Today.

Loeb said that based on the data, he would be "comfortable" with using the trivalent nasal spray vaccine in his patients: "There were no signals of any issue with the vaccine."

But that's apparently not the case with the quadrivalent version, Schaffner told MedPage Today.

At its June meeting, he said, the ACIP had vaccine efficacy data for three seasons:

In 2013-14, the first year of quadrivalent vaccines, the nasal spray "underperformed" compared with the injectable version, and it apparently had no effect on the dominant H1N1 influenza A strain

In 2014-15, all vaccines did poorly because the dominant circulating H3N2 influenza A strain was not matched by the vaccine strains, but the nasal spray did "spectacularly" worse than the injectable

In 2015-16, the nasal spray had "essentially no activity" against the H1N1 strain

Data from the drug's maker, AstraZeneca, showed a benefit in 2015-16, Schaffner said, but there was still a "large discrepancy" between efficacy for FluMist and for the inactivated vaccines.

Why remains an open question. "The manufacturing has been fine, so it's something more basic and scientific," Schaffner said.

One possibility is that the seed strain for the H1N1 component of the vaccine is compromised somehow, resulting in the observed suboptimal effect on circulating H1N1 influenza.

A second possibility is that having four strains of virus in the drug leads to some sort of interference as they multiply in the nasal passages and pharynx, with the result that the immune response is less powerful than expected.

And a third hypothesis is that the emphasis on childhood flu shots in recent years has resulted in a population of children who are "immunological adults" -- their immune systems, like those of grown-ups, have had enough experience with flu to fight off the mild infection caused by FluMist without developing further immunity.

None of those hypotheses is supported by any evidence, Schaffner noted.

The study was funded by the Canadian Institutes for Health Research and the Public Health Agency of Canada.

Loeb disclosed relationships with Sanofi Pasteur, AstraZeneca, and Novartis Vaccines and Diagnostics. Schaffner and Pavia did not disclose any relevant relationships.

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